학술논문
Discovery and Toxicological Profiling of Aminopyridines as Orally Bioavailable Selective Inhibitors of PI3-Kinase γ
Document Type
Article
Author
Bellenie, Benjamin R; Hall, Edward; Bruce, Ian; Spendiff, Matthew; Culshaw, Andrew; McDonald, Sarah; Ambarkhane, Ameet; Chinn, Colin; Thomas, Matthew; Rosner, Elisabeth; Bracher, Marguerite; Nicklin, Paul; Marshall, Stephen; Coote, Julie; Cullen, Eva; Tessier, Clemence; Wuersch, Kuno; Lal, Ajay; Wallis, Gillian; Hollingworth, Gregory J.; Neef, James
Source
Journal of Medicinal Chemistry; 20210101, Issue: Preprints
Subject
Language
ISSN
00222623; 15204804
Abstract
Using a novel physiologically relevant in vitro human whole blood neutrophil shape change assay, an aminopyrazine series of selective PI3Kγ inhibitors was identified and prioritized for further optimization. Severe solubility limitations associated with the series leading to low oral bioavailability and poor exposures, especially at higher doses, were overcome by moving to an aminopyridine core. Compound 33, with the optimal balance of on-target activity, selectivity, and pharmacokinetic parameters, progressed into in vivo studies and demonstrated good efficacy (10 mg/kg) in a rat model of airway inflammation. Sufficient exposures were achieved at high doses to support toxicological studies, where unexpected inflammatory cell infiltrates in cardiovascular tissue prevented further compound development.